Pupilary Screening System and Method

ABSTRACT

A method of screening a pupil of a subject to determine whether the pupil reflex resembles a canonical pupil reflex is disclosed. The method comprises the steps of stimulating the pupil with a stimulus source, such as a pupilometer and determining whether one of various pupillary response conditions is met.

RELATED APPLICATIONS

This is a continuation of U.S. application Ser. No. 14/571,276, filedDec. 15, 2014 which is a continuation of U.S. application Ser. No.13/543,341, filed Jul. 6, 2012 which is a continuation of U.S.application Ser. No. 12/210,185, filed Sep. 13, 2008, which claimspriority from U.S. Provisional Patent Application Ser. No. 60/972,636,filed Sep. 14, 2007.

The entirety of each of the foregoing patent applications areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to pupilometry systems and, moreparticularly, to pupilometry systems having a pupil irregularitydetection, pupil tracking, and pupil response detection capability, aswell as glaucoma screening capability, corneal topography measurementcapability, intracranial pressure detection capability, and ocularaberration measurement capability. In one particularly innovativeaspect, the present invention relates to hand-held pupilometry systemshaving a pupil irregularity detection capability, to methods andprocessing sequences used within such systems, and to methods of usingsuch systems.

In another innovative aspect, the present invention relates to a medicaldiagnostics system incorporating a pupilometer and medical database forcorrelating actual or derived pupilary image analysis data with storedmedical data to formulate medical diagnoses, and to methods ofimplementing and utilizing such a diagnostics system.

In another innovative aspect, the present invention relates to a medicaldiagnostics system incorporating a pupilometer which can be used toscreen for Glaucoma, and for methods of implementing and utilizing sucha diagnostics system.

In another innovative aspect, the present invention relates to a medicaldiagnostics system incorporating a pupilometer for detecting elevatedintracranial pressure, and for methods of implementing and utilizingsuch a diagnostics system.

In another innovative aspect, the present invention relates to a medicaldiagnostics system incorporating a pupilometer for assessing the levelof brain function, and for methods of implementing and utilizing such adiagnostics system.

In another innovative aspect, the present invention relates to a medicaldiagnostics system incorporating a pupilometer for testing thefunctional integrity of afferent peripheral and cranial pathways as wellas testing efferent cranial nerve involvement in patients with afferentpupilary defects, and for methods of implementing and utilizing such adiagnostics system.

In another innovative aspect, the present invention relates to a medicaldiagnostics system incorporating a pupilometer for testing thefunctional integrity of auditory pathways, and for methods ofimplementing and utilizing such a diagnostics system.

BACKGROUND OF THE INVENTION

Systems for monitoring pupil size and pupil responsivenesscharacteristics are well known in the art and are generally referred toas pupilometry systems or, simply, pupilometers. One early pupilometeris described in U.S. Pat. No. 3,533,683, which issued to Stark et al. onOct. 13, 1970 and is entitled “Dynamic Pupilometers Using TelevisionCamera System” (incorporated herein by reference). The Stark et al.system employed a television camera system, a digital computer system,an infrared light source, and a visual light stimulator for determiningthe instantaneous size of a pupil as an eye (or neurologic pupilarycontrol system) of a patient was exposed to various stimuli. Like theearly Stark et al. system, conventional pupilometers measure, forexample, the diameter of a pupil before and after the pupil is exposedto a light stimulus pulse and also measure the rates at which the pupilmay constrict and dilate in response to the initiation and terminationof the light stimulus pulse. Pupilometers may comprise hand-held unitsor, alternatively, may comprise desk or table-mounted, stand-aloneunits. Pupilometers also generally include some mechanism for ensuringthat an imager within the pupilometer is properly positioned in relationto a pupil to be imaged. For example, U.S. Pat. No. 5,646,709(incorporated herein by reference), issued to Elbert P. Carter,describes an electronic centering system for ensuring that a pupilometeris properly positioned in relation to a pupil to be imaged. Similarly,U.S. Pat. No. 5,187,506 (incorporated herein by reference), issued toElbert P. Carter, describes an eye orbit housing for ensuring properpositioning between a pupilometer and an eye of a subject prior to theinitiation of a pupilary scanning procedure.

Those skilled in the art will appreciate, however, that for apupilometer to have maximum utility maximum flexibility should beprovided for positioning the imager. For example, in the case of ahand-held system few, if any, restrictions should be placed upon theorientation of the imager prior to enabling an imaging function. Thereason for this is that medical personnel at, for example, an accidentsite may have difficulty in positioning an imager in a prescribedposition for acquiring pupilary response data. Thus, it is believedthat, for hand-held units in particular, a need exists within thepupilometer field for improved data acquisition and processing systemsand methods, as such systems and methods may substantially reduce systemdependence on imager orientation and may allow pupilometers to becomemore user friendly.

Similarly, those skilled in the art will appreciate that a need existsfor pupilometers that are capable of evaluating more than a merepupilary response to light stimulus pulses. For example, it is believedthat a substantial need exists for a pupilometer that is capable notonly of measuring changes in pupilary diameter in response to one ormore light stimulus pulses, but also of evaluating pupil shape and/orsegmental responses to a visual stimulus. Stated somewhat differently,it is believed that a substantial need exists for a pupilometer having apupilary shape irregularity or non-uniformity detection capability.

Finally, it is believed that a substantial need exists forpupilometer-based diagnostics systems, as such systems may providemedical practitioners with a cost effective, noninvasive means forgathering and assessing numerous physiologic parameters.

For example, the present invention can be used to screen for Glaucoma,which is the second leading cause of blindness in the world. Visualfield perimetry is presently used for diagnosing Glaucoma. In visualfield perimetry, a white background and multiple green flicker sourcesare used. The green sources are randomly turned on for approximately onesecond durations and the subject patient is asked to press a button ifhe/she sees a green light. The procedure is repeated until the entirevisual field is mapped for each eye. Loss of visual field sensitivity isindicative of Glaucoma.

The current standard of care for Glaucoma detection, however, suffersform inaccuracy and human/patient error. The current standard of carerelies on the patient to respond to his or her visual detection of greenlight by pressing a button. The patient has a limited window of time inwhich to respond to the green light. Thus, if the patient is notconcentrating or responds too quickly or too slowly, the perimetrydevice will not register the patient's response, and the accuracy of thediagnosis is compromised. Furthermore, current perimetry devices arelarge machines that are immobile. They are for use in doctors' officesonly. Thus, a need exists for improved systems and methods for Glaucomadetection, and the present invention meets these needs and solves theproblems associated with standard techniques.

Another area of diagnostic need relates to assessing the level of brainfunction to diagnose disorders such as autism, age-related disorders,and drug impairment or intoxication. Neurological exams today do nottypically include pupilometry beyond the use of a pin-light. Currently,expensive and/or time-consuming tests are required to diagnoseimpairment of brain function. And, the pin-light test is subjective,non-quantifiable, and inaccurate. The present invention solves these byproviding a method and system to closely track the pupil whilepresenting the eye with a moving visual stimuli to determine the levelof coordination. The present invention is capable of quantifyingtracking errors, which might occur in the course of a neurological exam,and reduces the subjectivity and increases the repeatability of exams toassess brain function.

Another area of diagnostic need is diagnosis of neurological disease ortrauma. Dermatome mapping of patients is commonly done with a pin-prickto determine the level of dorsal root or spinal cord injury. This test,however, is subjective and usually requires cognitive response from apatient. There exists a need for noninvasive diagnosis of neural damageor trauma. The present invention fills that need by providing a means ofquantitatively measuring pupilary response to noxious stimulation.Furthermore, this invention is useful in diagnosing dorsal root andspinal cord injuries in unconscious patients with no cognitive responsecapabilities. It is further useful in diagnosing and monitoring theprogression of demyelinating diseases such as multiple sclerosis, whichaffects conduction velocity through nerve fibers. In addition, testingthe level of epidural anesthetic block may be accomplished usingpupilometry with this automated stimulus control.

Finally, an area of diagnostic need relates to testing the functionalintegrity of auditory pathways, i.e., hearing screening. Particularlywith infants, hearing has been subjectively screened using stimuli suchas in a clap test while observing the startle response. Other tests,such as EEG-type brain stem audible evoked potential (AEP) monitoringsystems have been used, but require attachment of electrodes to thescalp and are cumbersome to use. Middle ear tone-feedback monitoring isalso used, but is not capable of measuring latency information. Thepresent invention solves these and other problems associated with theprior art by providing hearing screening using objectivepupilometer-based testing systems and methods. The pupilometer-basedsystems are not cumbersome, are easy to use and provide latencyinformation for diagnosing and monitoring the progression ofdemyelinating diseases.

SUMMARY OF THE INVENTION

In one particularly innovative aspect, a method of screening a pupil ofa subject to determine whether the pupil reflex resembles a canonicalpupil reflex. The method comprises the steps of stimulating the pupilwith a stimulus source is disclosed. The method further includes thesteps of using a pupilometer to track the pupil's constriction responseover a duration of time, wherein the step of tracking the pupilconstriction response begins substantially simultaneously with orimmediately subsequent to time 0 and lasts for a period of time y, andusing the pupilometer to collect a plurality of data points in whicheach data point corresponds with a diameter of the pupil at a specifictime within the time duration y. The method further includes the step ofgenerating a pupil data profile by compiling the data points anddetermining whether one or more conditions are met, wherein the one ormore conditions comprises the following: (a) more than two data pointsexist representing the same pupil diameter at three or more separatetimes during duration y; (b) a first phase of the pupilary reflexresponse exists, wherein said first phase is characterized by a periodof non-constriction immediately subsequent to time 0, said first phasehaving a duration of less than about 100 msec or greater than about 1000msec; (c) two data points exist representing the same pupil diameter attwo separate times y¹ and y² during duration y, wherein the duration oftime between y¹ and y² is less than about 100 msec; or (d) during thefirst phase of the pupilary reflex, the diameter of the pupil increasesbefore it decreases. Existence of one of said conditions indicates thatthe pupil reflex does not resemble a canonical reflex.

In another innovative aspect, another method of screening a pupil of asubject to determine whether the pupil reflex resembles a canonicalpupil reflex is disclosed. The method comprises the steps of stimulatingthe pupil with a stimulus source is disclosed. The method furtherincludes the steps of using a pupilometer to track the pupil'sconstriction response over a duration of time, wherein the step oftracking the pupil constriction response begins substantiallysimultaneously with or immediately subsequent to time 0 and lasts for aperiod of time y, and using the pupilometer to collect a plurality ofdata points in which each data point corresponds with a diameter of thepupil at a specific time within the time duration y. The method furtherincludes the step of generating a pupil data profile by compiling thedata points and determining whether the following four conditions aremet: (a) no more than two data points exist representing the same pupildiameter at separate times during duration y; (b) a first phase of thepupilary reflex response exists, wherein said first phase ischaracterized by a period of non-constriction immediately subsequent totime 0, said first phase having a duration of greater than about 100msec and less than about 1000 msec; (c) if two data points existrepresenting the same pupil diameter at two separate times y¹ and y²during duration y, then the duration of time between y¹ and y² isgreater than about 100 msec; and (d) during the first phase of thepupilary reflex, the diameter of the pupil does not increase before itdecreases. The absence of one of the four conditions indicates that thepupil reflex does not resemble a canonical reflex.

Other objects and features of the present invention will become apparentfrom consideration of the following description taken in conjunctionwith the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of a hand-held pupilometer inaccordance with a preferred form of the present invention.

FIG. 2 is an illustration of a liquid crystal display and keypad thatmay be provided on a hand-held pupilometer in accordance with thepresent invention.

FIG. 3 is an enlarged cross-sectional view of an imaging section of ahand-held pupilometer in accordance with the present invention.

FIG. 4 is a three-dimensional plan view showing a preferred arrangementof a plurality of IR, blue and yellow LEDs that may be used for ocularillumination and stimulation within a pupilometer in accordance with thepresent invention.

FIG. 5 is a block diagram illustrating a group of programming objectsthat preferably comprise an operating program of a pupilometer inaccordance with the present invention.

FIG. 6 is a timing diagram illustrating a typical stimulus/illuminationsequence for the IR, blue and yellow LEDs that may be used within apupilometer in accordance with the present invention.

FIGS. 7(a) and 7(b) are illustrations of histogram data sets that may bedeveloped in accordance with a preferred thresholding algorithm utilizedby a pupilometer in accordance with the present invention.

FIGS. 8(a) and 8(b) depict a flow chart illustrating a basic operatingprotocol for a pupilometer in accordance with the present invention,with FIG. 8(b) depicting a continuation of the flow chart begun in FIG.8(a).

FIG. 9 is an illustration of a pupilometer incorporating a consensualmeasurement attachment in accordance with the present invention.

FIG. 10 is a cross-sectional view of a hand-held pupilometer inaccordance with yet another embodiment of the present invention.

FIG. 11 is a front view of the diode array depicted in FIG. 10.

FIG. 12 is a front view of a diode array in accordance with anotherembodiment of the present invention.

FIG. 13 is a cross-sectional view of a direct-view hand-held pupilometerin accordance with another embodiment of the present invention.

FIGS. 14a-14f are graphical representations identifying the phasescharacterizing a standard pupil light constriction reflex and a methodfor screening for a non-responsive or non-canonical pupilary response.

DESCRIPTION OF PREFERRED EMBODIMENTS

A. Hardware Components of a Pupilometer in Accordance with the PresentInvention

Turning now to the drawings, FIG. 1 provides a cross-sectional view of ahand-held pupilometer 10 in accordance with the present invention. FIG.2 provides an illustration of a liquid crystal display and key pad thatmay be provided on the hand-held pupilometer 10, and FIG. 3 is anenlarged cross-sectional view of an imaging section of the hand-heldpupilometer 10.

As shown in FIGS. 1-3, the pupilometer 10 preferably includes a housing12 wherein an imaging sensor 14, an objective lens 16, first and secondbeam splitters 18 and 20, a shield 22, four infrared (IR) LEDs 24, twoyellow LEDs 26, a blue LED 28 (shown in FIG. 4), a reticle 30, a battery32, an image signal processing board 34 and a liquid crystal display 36are mounted. Stated somewhat differently, the pupilometer may comprise aviewing port (reticle 30 and shield 22), an imaging system (objectivelens 16, imaging sensor 14 and related image processing electronics), anillumination system (IR LEDs 24, blue LED 28 and related controlcircuitry) and a stimulus system (yellow LEDs 26 and related controlcircuitry).

Other embodiments that include some or all of the aforementionedelements are shown in FIGS. 10 and 13. In FIG. 10, the pupilometer 300further includes a lenslet array 330, and a diode array 340. In FIG. 13,the pupilometer 400 has all of the components of the pupilometer 10,except that it does not have beam splitters, a viewing reticle, blueLEDS, or yellow LEDS. It does, however, contain white LEDS, now shown, afilter glass 418, and an auxiliary connecter 415.

1. The Viewing Port

The viewing port (reticle 30 and shield 22) is provided to aid a user inproperly positioning the pupilometer 10 for initial data acquisition. Bylooking through the reticle 30 and shield 22, the user of thepupilometer 10 is able to properly position the pupilometer 10 in frontof an eye 38 of a patient, such that an image of the pupil of thepatient's eye may be projected onto the imaging sensor 14. The reticle30 preferably has circular targets (not shown) silk screened or etchedon one surface. The targets are positioned along the user's line ofsight so as to appear concentric with the iris and pupil of an eye 38under observation.

Those skilled in the art will appreciate that the reticle 30 and shield22 also serve as environmental barriers and function to minimizeexposure of the imaging system to caustic cleaning agents, biologicalmaterial and airborne dust, all of which can have a negative impact uponthe performance of the imaging system.

Pupilometers 300 and 400, as shown in FIGS. 10 and 13 respectively, donot contain a viewing port as described in connection with pupilometer10. In pupilometers 300 and 400, the reticle and viewing port have beenreplaced by functions of the LCD. For example, in FIG. 13, the LCD 436provides a low frame rate image of the eye during the targetingprocedure with graphical indications that the software has detected theiris and pupil. The frame rate can be 6 frames per second, morepreferably 10 frames per second, more preferably 25 frames per second,more preferably 50 frames per second, more preferably 100 frames persecond, more preferably 200 frames per second, and most preferably 500frames per second.

An electronic window, which helps the user center the subject's eye, isalso provided during the targeting phase. In the process of targeting,an image of the eye is displayed on the LCD 436. Graphical aids, such asblack lines or boxes are displayed to help position the device over theeye. The image on the LCD is updated at a rate of about 6 frames persecond, more preferably 10 frames per second, more preferably 25 framesper second, more preferably 50 frames per second, more preferably 100frames per second, more preferably 200 frames per second, and mostpreferably 500 frames per second.

The LCD 436 can be monochromatic or color. A color LCD 436 can improvethe targeting process by providing graphical feedback about the qualityof the tracking/imaging in a different color than that represented bythe eye.

2. The Imaging System

The imaging sensor 14 preferably comprises a N×M bit CMOS imaging sensorof a type that is commercially available. One such imaging sensor is the384×288 bit, Model OV5017, CMOS imaging sensor manufactured anddistributed by Omnivision Technologies, Inc. of Sunnyvale, Calif. Theimaging sensor 14 is mounted to an imager board 31 of the pupilometer 10and is coupled to a microprocessor (not shown) provided on a mainprocessing or mother board 34 of the pupilometer 10. This allows fordirect capture of digital images. Images in the form of 8 bit (orgreater) gray scale bit maps are stored in system memory for imageanalysis and display on the liquid crystal display 36 (shown in FIG. 2).The microprocessor (not shown) preferably comprises an Elan SC 400manufactured and distributed by Advanced Micro Devices, Inc., of Austin,Tex.

The imaging system of the present invention is designed such that, whenthe hand-held pupilometer 10 is positioned in front of the eye 38 of asubject, a properly illuminated and in-focus image of the pupil 43 ofthe subject's eye 38 is obtained at the sensor plane 40 of thepupilometer 10. The objective lens 16 and a first beam splitter (i.e.,wavelength selective filter) 18 preferably are used to focus an image ofthe pupil 43 of the subject's eye 38 on the sensor plane 40. In apreferred form, the objective lens 16 comprises a five element lenshaving a focal length of 7.0 mm. The first beam splitter 18 preferablycomprises a glass substrate having a thickness of 1.6 mm that is coatedwith a multi-layer dielectric coating (not shown) to form a wavelengthselective filter. The subject side 42 of the beam splitter 18 is coatedto enhance reflection at the blue and infrared (IR) wavelength bandswith a 45° angle of incidence. The user side 44 of the beam splitter 18is AR coated to minimize effects resulting from multiple reflections inthe image path.

Thus, as shown in FIGS. 1 and 3, the beam splitter 18 functions todirect blue and/or IR light generated by the blue and IR LEDs 28 and 24,respectively, toward the eye 38 of a patient and to provide a returnpath to the imaging sensor 14 for blue and/or IR light that is reflectedfrom the eye 38 of the patient.

The microprocessor (not shown) provided on the main signal processingboard 34 controls the operation and function of the various componentscomprising the imaging system as described more fully below.

The imaging system of the pupilometer 300 shown in FIG. 10 is similar tothat described with respect to pupilometer 10. The beam splitter 318,imaging sensor 314 including imaging plane 340, and objective lens 316,each can be of the same type as beam splitter 18, imaging sensor 40including imaging plane 14, and objective lens 16 respectively. Theobjective lens 316 and beam splitter 318 are used to focus an image ofthe pupil of the subject's eye on the sensor plane 340.

Pupilometer 400, as shown in FIG. 13, functions in the same mannerexcept that a beam splitter is not needed to direct an image of thepupil of the subject's eye on the sensor plane 440. Light passes throughfilter glass 418 and objective lens 416, which together focus an imageof the pupil on sensor plane 440. The sensor plane 440 is part of theimaging sensor 414. Furthermore, the filter glass 418 is in directcontact with and mounted on the objective lens 416. The filter glass 418can remove all spectral components except for IR light. It can alsoimprove the image contrast at the sensor and reduce variation in ambientlight conditions, which can also affect performance.

Thus, as shown in FIG. 10, the beam splitter 318 functions to directblue and/or IR light generated by the blue and IR LEDS, 328 and 324respectively, toward the eye of a patient, and to provide a return pathto the imaging sensor 314 for blue and/or IR light that is reflectedfrom the eye of the patient.

3. The Illumination System

With respect to pupilometers 10, 300, and 400, the illumination systempreferably comprises a blue light emitting diode (LED) 28 and 328respectively (not shown with pupilometer 400 in FIG. 13), and fourinfrared (IR) LEDs 24, 324, and 424 respectively. Although not shown inpupilometer 400, it too can include a blue LED mounted in the samemanner as in pupilometers 10 and 300. The IR LEDs 24, 324, and 424preferably are arranged symmetrically about the objective lens 16, 316,and 416 respectively. The IR LEDs 24 and blue LED 28 are coupled to aflex circuit 33 that is coupled to the main signal processing board 34of pupilometer 10. Although not shown in FIGS. 10 and 13, the same istrue for pupilometers 300 and 400. When activated by the microprocessor(not shown), the IR LED's 24 emit IR light preferably having awavelength of substantially 850 nm. Again, this is also true withrespect to the IR LEDS in pupilometers 300 and 400. Thus, those skilledin the art will appreciate that the emission bandwidth of the IR LEDslies beyond the physiological response of the human eye but within thephotoelectric response of the imaging sensors 14, 314, and 414. Statedsomewhat differently, while the human eye is unable to detect the IRlight emitted by the IR LEDs, IR light generated by the IR LEDs andreflected by the eye 38 of a subject may be detected by the imagingsensors.

The four IR LEDs 24, 324, and 424 in each of pupilometers 10, 300, and400 respectively, preferably are arranged in diametrically opposedgroups of two, as shown in FIG. 4. By arranging the IR LEDs in themanner shown in FIG. 4, it is possible to more precisely control the IRillumination of a patient's eye 38 and, moreover, to achieve levels of0, 50 and 100% illumination, if desired. Again, this desired arrangementapplies equally to pupilometers 300 and 400. The only difference withpupilometers 300 and 400 is that they do not have yellow LEDS 26, butinstead have white LEDS, which are not shown in FIGS. 10 and 13, butwhich are disposed around objective lenses 316 and 416 in the samemanner as yellow LEDS 26 are disposed around objective lens 16.

The blue LEDs are used for ocular illumination in situations where thesclera/iris border of a patient's eye 38 may be difficult to detect withIR illumination alone. As shown in FIG. 4, the blue LED 28 preferably isplaced on the same radial arc that is defined by the IR LEDs 24, whichsurround the objective lens 16. The blue LED 28, when activated by themicroprocessor (not shown), preferably emits light having a wavelengthof substantially 470 nm. The same is true for the blue LEDS associatedwith pupilometers 300 and 400. Thus, blue LEDS 328 are preferably placedon the same radial arc that is defined by the IR LEDS 324, whichsurround the objective lens 316. Blue LEDS 328 also emit light having awavelength of substantially 470 nm. And the blue LEDS associated withpupilometer 400 (not shown) also emit a light having a wavelength ofsubstantially 470 nm, and are also preferably placed in an arc that isdefined by the IR LEDS 424, which surround objective lens 416.

It has been discovered by the inventors hereof that light in the bluecolor band may be used to substantially improve sclera/iris border imagecontrast because the iris 37 and sclera 41 of a subject's eye 38generally have substantially different light absorption and reflectioncharacteristics in the blue color band. Thus, the use of a blue LED forsclera/iris border imaging is believed to be a particularly innovativeaspect of the present invention.

Because the human eye is responsive to blue radiation, the blue LEDspreferably are only activated for brief periods of time in relation tothe temporal response of a subject's eye 38 or, alternatively, is usedin conjunction with the stimulus LEDs 26 (not shown with pupilometers300 and 400) described below. Moreover, in a preferred form, IR and bluelight illumination of the eye 38 of a subject may be performed in amultiplexed fashion, such that the eye of the subject is illuminatedwith IR light for a first period of time and, thereafter, illuminatedwith blue light for a second period of time. This is discussed morefully below with reference to FIG. 6.

The microprocessor (not shown) provided on the main signal processingboard 34 controls the operation and function of the various componentscomprising the illumination system as described more fully below.

4. The Stimulus System

The stimulus system of the pupilometer 10 comprises two yellow LEDs 26and a second beam splitter 20. The yellow LEDs 26 preferably are coupledto the flex circuit 33 and, when activated by the microprocessor (notshown), emit light having a wavelength of substantially 570 nm. Like thefirst beam splitter 18, the second beam splitter 20 preferably comprisesa glass substrate having a thickness of 1.6 mm and is coated with amulti-layer dielectric coating (not shown) to form a wavelengthselective filter. The subject side 50 of the beam splitter 20 is coatedto enhance reflection at the yellow wavelength band with a 45° angle ofincidence, and the user side 52 of the beam splitter 20 is AR coated tominimize effects resulting from multiple reflections in the user'sobservation path. The stimulus system of the pupilometer 10 preferablyprovides on-axis illumination of the pupil 43 of the eye 38 of apatient, as shown in FIG. 1.

The stimulus system of pupilometer 300 can comprise yellow LEDS as inpupilometer 10, or white LEDS (not shown). These yellow or white LEDSoperate in the same manner as those in pupilometer 10. Additionally,however, pupilometer 300 includes a lenslet array 330, and a diode array340, which add an additional stimulus function. The diode array 340functions in the detection of glaucoma by providing blue light fromseries N concentrated (optically) blue LEDS 320, which can be imagedonto the retina in such a way as to stimulate N specific regions of theretina. The lenslet array 330 focuses the light through the beamsplitter 318 appropriately so that the blue light that is emittedreaches a known area of the retina. Furthermore, the diode array 340 hasa diffuse yellow light emitting surface 310 to bias the background asyellow against the blue flicker sources 320.

The stimulus system of pupilometer 400 can also comprise yellow LEDS asin pupilometer 10, but more preferably comprises white LEDS (not shown).In pupilometer 400, there are four white LEDS that are placedsymmetrically among the IR LEDS 424. Thus, a total of eight LEDS areplaced around the objective lens 416 on a common radial displacementfrom the optical axis of the objective lens 416.

B. Software Components of a Pupilometer in Accordance with the PresentInvention

The following description of the software applies to pupilometers 10,300, and 400, but will only be described in connection with pupilometer10 for convenience and brevity. It should be understood, however, thatthe software and microprocessor components described herein are designedfor use with each of the pupilometers disclosed herein.

Turning now to FIGS. 5-7, a pupilometer 10 in accordance with thepresent invention is a microprocessor based system and, therefore,preferably includes several software components or modules forcontrolling its operation. As is well known in the art, an operatingsystem provides fundamental machine level interfaces between thehardware elements comprising the pupilometer 10. More specifically,various device drivers are used to provide an interface between themicroprocessor (not shown) and the imaging sensor 14, IR LEDs 24, yellowLEDs 26, blue LED 28, keypad 39 and liquid crystal display 36.

The highest level of programming or code used within the pupilometer 10is referred to herein as the P-Program, and the P-Program preferably isdivided into five principal objects corresponding to different hardwareand mathematical components. The five principal objects are illustratedin block diagram form in FIG. 5 and preferably include a graphic userinterface (GUI) object 100, a stimulus/illumination object 102, a CMOScamera object 104, a feature extraction object 106 and an analysisobject 108. All of the above-listed objects preferably are developed inMicrosoft Visual C++ and Windows CE, and the graphic user interface(GUI) object 100 preferably is based on Win32 Api functions that areavailable in Windows CE. Visual C++ and Windows CE are software productsdistributed by Microsoft Corp. of Redmond, Wash.

1. Graphic User Interface (GUI) Object

The graphic user interface object 100 allows for data/informationexchange between a user and the pupilometer 10. Information relating tothe current status of the pupilometer 10 including mode of operation(i.e., direct or consensual response, left or right eye measurementetc.) and the battery level is displayed via the graphic user interfaceobject 100. All inputs and outputs of the pupilometer 10 preferably arecoordinated via the graphic user interface object 100. Verification ofsubject ID numbers and/or patient identification data may beaccomplished under control of the graphic user interface object 100.Measurement parameters are determined and set with the assistance of thegraphic user interface object 100. Instructions during measurementsequences and images of the iris 37 of the eye 38 of a subject areprovided on the liquid crystal display 36 under control of the graphicuser interface object 100. Similarly, results of measurement sequencesare displayed on the liquid crystal display 36 under control of thegraphic user interface object 100, and the option to transfermeasurement results to a printer or network computer (not shown) isavailable through the graphic user interface object 100.

2. Stimulus/Illumination Object

The stimulus/illumination object 102 defines and controls the functionof the yellow LEDs 26, IR LEDs 24 and blue LED 28 and, therefore,controls the stimulation and illumination of the eye 38 of a subject.The stimulus/illumination object 102 defines the various light profiles(i.e., yellow, IR and blue) as a function of time and controlsactivation of the yellow, IR and blue LEDs 26, 24 and 28, accordingly.In a typical stimulus/illumination sequence, the LEDs 26, 24 and 28preferably are activated in the manner described below. However, thoseskilled in the art will appreciate that the stimulus/illuminationsequence may be varied depending upon the circumstances of any givensituation, and that variations in the stimulus/illumination sequence maybe effected through the user interface object 100.

During a typical stimulus/illumination sequence, the LEDs 24, 26 and 28may be operated as shown in FIG. 6. For example, during a typicalmeasurement sequence, the yellow LEDs 26 may be activated anddeactivated for successive 1 second intervals (i.e., “on” for 1 secondand “off” for 1 second) for a period of 10 seconds total.Simultaneously, the IR LEDs 24 may be activated for all periods when theyellow LEDs 26 are “off,” and may be deactivated, activated anddeactivated (i.e., turned “off,” “on” and “off”) for respective 0.04,0.92 and 0.04 second intervals, while the yellow LEDs 26 are turned“on.” Similarly, the blue LED 28 may be activated, deactivated andactivated for respective 0.04, 0.92 and 0.04 second intervals, while theyellow LEDs 26 are turned “on,” and may be deactivated during allperiods when the yellow LEDs are turned “off” This allows for theoperation of the IR LEDs 24 and blue LED 28 to be multiplexed. In suchan embodiment, the image frame transfer rate preferably would be set,for example, to 50 frames per second.

3. The CMOS Camera Object

The CMOS camera object 104 controls the transfer of image data framesbetween the CMOS imaging sensor 14 and memory associated with themicroprocessor (not shown) provided on the main signal processing board34 (i.e., between the imaging sensor 14 and the P-Program). Preferably,the rate of image frame transfer between the imaging sensor 14 and thememory associated with the microprocessor (not shown) may beprogrammably set within a range from 1 frame per second to 50 frames persecond, depending upon the needs and/or desires of the user. However,those skilled in the art will appreciate that in some instances it maybe desirable to provide for faster frame transfer rates, and that suchrates might be as high or higher than 100 frames per second. The imageframe acquisition or transfer rate is defined by the user under controlof the graphic user interface object 100.

4. The Feature Extraction Object

The feature extraction object 106 defines several image processingprocedures that are used to isolate a pupil within an image and toextract several pupil features such as size, shape and position fromeach pupil image data frame. All processing procedures defined by thefeature extraction object preferably are performed on each image dataframe, with the exception of the automatic thresholding proceduredescribed below. The automatic thresholding procedure is applied duringan initial calibration phase and, therefore, does not need to be appliedto each image data frame. Rather, the results of the automaticthresholding procedure are used during feature extraction processing foreach image data frame. The results of the automatic thresholdingprocedure also may be used to set and/or adjust image exposure gainsettings within the system.

The feature extraction object 106 employs a flying spot processingalgorithm to identify the center of the pupil, a fitted circumferenceand/or radius of the pupil and, preferably, 48 radii representing thedistance between the center and perimeter of the pupil at 48 separateangles in an R,θ coordinate system, where θ defines an angularorientation about the center of the pupil, and R represents the radiusof the pupil at that orientation. The fitted radius of the pupil isdetermined by selecting a circumference that best fits a contour of thepupil and by solving the equation 2πr to obtain the radius value (r).

Those skilled in the art will appreciate that, by defining andevaluating 48 distinct radii about the center of the pupil, it ispossible in accordance with the present invention to detect one or morenon-uniformities or irregularities that may exist around the perimeterof the pupil. It also is possible to characterize the shape of the pupilas circular, elliptical etc. based upon the determined radii. It also ispossible to evaluate selected sections of a pupil perimeter to determinewhether or not those sections exhibit normal contour characteristicsand/or normal responses to visual stimulus. It is believed that thesecapabilities represent significant improvements over conventionalpupilometry systems, as these features allow not only for theperformance of conventional pupil aperture and response evaluations, butalso for the performance of pupil shape and sectional contourevaluations. Thus, where a particular affliction may produce a definedirregularity in pupil shape or defined sectional response to visualstimulus, the affliction may be identified through the use of apupilometer in accordance with the present invention.

The inputs to, and outputs obtained from, the flying spot algorithm maybe defined as follows:

Input Parameters:

-   -   Frame=eye image frame generated by the CMOS imaging sensor 14    -   Threshold=gray level threshold value; any pixel having a gray        scale value greater than the threshold value is considered to be        part of the pupil.

Output Parameters:

-   -   Output=fitted radius and center of pupil, 48 radii.

It is assumed herein that within the gray scale used by the pupilometer10 the color black will be associated with a high gray scale value, suchas 255, and the color white will be associated with a low gray scalevalue, such as 0. However, those skilled in the art will appreciate thatthe relative maximum and minimum values could be reversed.

It is believed that the use of flying spot algorithms are well known inthe art and, therefore, that the flying spot algorithm need not bedescribed in detail herein. Nonetheless, the basic flying spot proceduremay be described as follows. The flying spot procedure starts with alarge circumference centered on the image of an eye and iterativelyreduces the size of the circumference. In reducing the size of thecircumference and adjusting the center location of the circumference,for each iteration the following momentums will be computed:

${\mu \; x} = {1\text{/}N*{\sum\limits_{x,y}{{gray\_ level}{\_ sign}\left( {x,y} \right)\left( {x - {x\; 0}} \right)}}}$${\mu \; y} = {1\text{/}N*{\sum\limits_{x,y}{{gray\_ level}{\_ sign}\left( {x,y} \right)\left( {y - {y\; 0}} \right)}}}$${\mu \; r} = {1\text{/}N\mspace{14mu} {\sum\limits_{x,y}{{gray\_ level}{\_ sign}\left( {x,y} \right)}}}$

where N represents the number of pixels having coordinates x,y in thecircumference contour; gray_level_sign(x,y) is +1, if the gray levelvalue of the pixel (x,y) is greater than the threshold value;gray_level_sign(x,y) is −1, if the gray level value of the pixel (x,y)is less than the threshold value; and x0,y0 are the center coordinatesof the circumference.

The x and y coordinates of the circumference center and the radius areupdated as follows:

x0=x0+μx*Gain_x

y0=y0+μy*Gain_y

radius=radius+μr*Gain_r.

As indicated above, the updating procedure is applied iteratively, eachtime calculating the momentum and then changing the center and radius ofthe flying spot, such that the circumference finally converges to acircumference that best fits the contour of the pupil.

Once the fitted radius and center of the pupil are determined, 48 radiirepresenting the distance between the center and perimeter of the pupilat 48 separate angles in an R,θ coordinate system preferably aredetermined, where θ defines an angular orientation about the center of apupil, and R represents the radius of the pupil at that orientation. Byevaluating the 48 determined radii, it is possible to characterize theoverall shape of the pupil and to determine whether or not any sectionalnon-uniformities or irregularities are present about the perimeter ofthe pupil. Such processing may be performed either by the featureextraction object 106 or the analysis object 108.

Another principal function performed by the feature extraction object isthresholding. The thresholding function automatically identifies a graylevel value that separates the pupil from the background in an imagedata frame. Moreover, when an appropriate threshold value is determined,all pixels having a gray level value greater than the threshold valueare considered to comprise part of the image of the pupil, and allpixels having a gray level value less than the threshold are consideredto correspond to background.

Preferably, the defined threshold value represents the average of amaximum hypothetical threshold value and a minimum hypotheticalthreshold value. The maximum and minimum hypothetical threshold valuesare derived through respective histogram analysis routines. Moreover, asshown in FIGS. 7(a) and 7(b), for each hypothetical threshold value twohistograms are evaluated, one for the rows of pixels within an imageframe, and one for the columns of pixels within the image frame. Thehistogram value for a given row or column is determined by counting thepixel locations in that row or column that have a gray level value thatexceeds the hypothetical threshold level. Thus, the number of valueswithin a histogram preferably corresponds to the number of rows orcolumns in the image data frame, and each value represents the number ofpixels in the specific row or column that have a gray level exceedingthe hypothetical threshold value.

Turning now in particular to FIGS. 7(a) and 7(b) the hypotheticalmaximum and hypothetical minimum threshold values are determined byiteratively altering a hypothetical threshold value until a prescribedhistogram profile is achieved. An acceptable profile is illustrated inFIG. 7(a) and is one in which a null-high-null pattern is achieved forboth a row histogram (y Hist) and column histogram (x Hist). Morespecifically, an acceptable profile preferably comprises a single “high”bordered by a pair of “nulls.” Unacceptable profiles are illustrated,for example, in FIG. 7(b).

The hypothetical maximum threshold value is determined by selecting anabsolute maximum value and iteratively decreasing that value andderiving corresponding histogram data sets until acceptable row andcolumn histogram profiles are achieved. Similarly, the hypotheticalminimum threshold value is determined by selecting an absolute minimumvalue and iteratively increasing that value and deriving correspondinghistogram data sets until acceptable row and column histogram profilesare achieved. Once the hypothetical maximum and minimum threshold valuesare determined, those values are averaged to determine the definedthreshold value that will be used by the feature extraction object 106.Those skilled in the art will appreciate that the defined thresholdvalue may correspond to the maximum hypothetical threshold value, theminimum hypothetical threshold value, or any value that is between thosevalues. Thus, in alternative embodiments, the defined threshold valuecould be determined, for example, based on a weighted average of themaximum and minimum hypothetical threshold values. In such anembodiment, the defined threshold value may comprise a valuecorresponding to the sum of the minimum hypothetical threshold value and⅔ of the difference between the maximum and minimum hypotheticalthreshold values.

5. The Analysis Object

The analysis object 108 analyzes the configuration characteristics of apupil as a function of time. Preferably, the analysis object 108receives, as inputs, from the feature extraction object 106 a pluralityof data sets for each captured image data frame. The data setspreferably include the time of image capture in msec, x and ycoordinates of the pupil center, radius of the flying spotcircumference, 48 radii representing the distance between the center andborder of the pupil for 48 selected angles within an R,θ coordinatesystem, and an applied stimulus record for the relevant entry. Uponreceiving the input data sets, the analysis object 108 preferablyderives at least the following information from the data sets: minimumpupil aperture, maximum pupil aperture, difference between maximum andminimum pupil apertures, latency of pupil response to yellow lightstimulus, pupil constriction velocity, first and second pupil dilationvelocities and, if desired, pupil irregularity magnitude and locationinformation. Where pupil irregularities are detected, the location ofthe irregularity preferably is identified by its θ coordinate. However,graphical indications also may be provided on the display 36 of thepupilometer 10.

Further, in alternative embodiments, the analysis object 108 may includeprogramming for effecting a multi-varied analysis wherein a plurality ofselected variables including, for example, latency indicia, constrictionvelocity indicia, first and second dilation velocity indicia, segmentalstatic and/or dynamic analysis indicia, constriction/dilation velocityratio indicia, and maximum and minimum diameter indicia are evaluatedfor one or both eyes of a patient to arrive at one or more scalar valuesthat are indicative of an overall physiologic or pathologic condition ofthe patient or, alternatively, to arrive at one or more scalar valuesthat are indicative of an overall opto-neurologic condition of thepatient.

With regard to the information derived by the analysis object 108, themaximum pupil aperture, minimum pupil aperture and differencedeterminations require the identification of the maximum pupil apertureand minimum pupil aperture within a set of image data frames and,thereafter, computation of the difference between those values. Thelatency determination provides an indication in milliseconds of the timethat it takes for a pupil to begin to respond to a visible (i.e.,yellow) light stimulus pulse. Further, those skilled in the art willappreciate that, when a pupil is exposed to a visual light stimuluspulse, the pupil generally will, after some latency period, constrictand, once the stimulus is discontinued, dilate and return to itsoriginal size and configuration. Thus, the analysis object 108 evaluatesthe response of a pupil to a visual stimulus to determine a pupilconstriction velocity and evaluates the response of the pupil totermination of the stimulus to determine first and second dilationvelocities. First and second dilation velocities are evaluated because apupil generally will dilate quickly for a first period of time and,thereafter, will dilate more slowly until its original size andconfiguration are achieved. Finally, as explained above, an analysisobject 108 in accordance with the present invention also preferablyidentifies any irregularities in the shape of the pupil. Suchirregularities may be either static or dynamic in nature. For example, astatic irregularity may take the form of an irregular pupil shape inambient light, whereas a dynamic irregularity may take the form ofincreased latency for a particular section of the pupil during aresponse to a the initiation or termination of a visual stimulus. Withregard to static irregularities, such irregularities may be identifiedby identifying the angular orientations of radii that do not fall withinprescribed limits, differ from other calculated radii by a predetermineddeviation or differ from the fitted radius by a predetermined amount,deviation or percentage.

Finally, an analysis object 108 in accordance with the present inventionpreferably includes programming for identifying statistical anomalieswithin derived results. This allows an analysis object 108 in accordancewith the present invention to discard either actual pupilary responsedata sets (i.e., fitted radius, center and radii calculations) orderived data sets (i.e., max aperture, min aperture, latency,constriction rate or dilation rates) when a selected value differs fromother values by a statistically significant degree. When such anomaliesare identified, the relevant data sets are not included in averagingfunctions, and where many anomalies are identified, an imaging sequencewill be invalidated and must be repeated.

C. Operation of a Pupilometer in Accordance with the Present Invention

The following description of the operation of a pupilometer of thepresent invention applies to each of pupilometers 10, 300, and 400, butwill only be described in connection with pupilometer 10 for convenienceand brevity. It should be understood, however, that the software andmicroprocessor components of each of pupilometers 10, 300, and 400 canbe the same, and therefore, the operation of each of these pupilometerscan be the same.

Turning now to FIG. 8, operation of a pupilometer 10 in accordance withthe present invention proceeds as follows. Generally the pupilometer 10will be configured according to a default mode of operation. The defaultmode defines a set of values for basic operation of the device. Thedefined values may include, for example, values for scan duration,illumination duration and/or profile, stimulus duration and/or profileand stimulus intensity level. However, it will be appreciated that allof the above-listed values may be programmably set under control of thegraphic user interface object 100. Thus, it will be appreciated thatdefault programming values generally will be utilized by the pupilometer10 absent entry of an override by the user in a scan sequence programmode.

A typical image acquisition and analysis procedure may proceed asfollows. If the pupilometer 10 has been idle for a predetermined periodof time (e.g., 120 seconds), the pupilometer 10 is automatically placedin a battery-conserving sleep mode (step 202). By depressing the “scan”button 45 (shown in FIG. 2), the user causes the pupilometer 10 to entera “ready” mode (step 200). At this time, the user is prompted to enteran alphanumeric subject or patient identification number via the keypad39 or to download any necessary patient information from a networkcomputer via an infrared data interface, such as an IrDA interface thatis provided on numerous conventional personal computer products (step204). Once any requisite patient identification data has been enteredinto the system, the user is prompted via the liquid crystal display 36or an audio prompt to hold down the “scan” button 45 and to position thepupilometer 10 in front of the eye 38 of a subject (step 210).

When the user depresses the “scan” button 45, the microprocessor (notshown) initiates an imaging test sequence. The yellow LEDs 26 preferablyare not activated during the test sequence. During the test sequence theimages that are acquired by the imaging sensor 14 may be displayed onthe liquid crystal display (LCD) 36. Preferably, the P-program analyzesthe image data frames that are acquired during the test sequence,determines whether or not the pupilometer 10 is properly positioned forobtaining measurements, and determines if all necessary parameters aremet to ensure high-quality data recovery. If the test criteria are notmet, the user is prompted to reposition the pupilometer 10. After anyrequisite test criteria are met, the P-program will continue to run thetest sequence until the “scan” button 45 is released.

Once the scan button 45 is released, the P-program preferably willinitiate a prescribed measurement sequence and will activate theillumination system of the pupilometer 10 as needed during themeasurement sequence. Upon completion of the measurement sequence, theuser is informed via the LCD 36 or an audio prompt that the measurementsequence has been completed (steps 226-228).

Following completion of the measurement sequence, the P-programpreferably will analyze the image data frames that have been obtainedand will display the results of the analysis on the LCD 36. If theresults are satisfactory (i.e., are statistically sound), the user maythen be prompted to download the results to a printer or related networkvia the IrDA interface (not shown) (step 246). If the results are notsatisfactory, the user is prompted to repeat the measurement sequence(step 222).

Finally, after an initial set of measurement are obtained, the user maybe prompted for a decision to measure the pupilary characteristics ofthe other eye of the subject/patient, or the user may be prompted for adecision to make a consensual response measurement (steps 238, 242). Theconsensual response measurement may take the form of a “swingingflashlight” measurement discussed more fully below. If a consensualmeasurement is to be performed, the user may be prompted to couple aconsensual measurement attachment (shown in FIG. 9) to the pupilometerand to position a yellow LED 52 mounted on the attachment in front ofthe appropriate eye of the subject/patient. If the consensualmeasurement attachment is permanently affixed to the pupilometer 10, theuser may only need to deploy and/or properly position the attachment.

D. Incorporation of Consensual Measurement Apparatus in a Pupilometer inAccordance with the Present Invention

The following description of incorporated consensual measurementapparatus applies to pupilometers 10, 300, and 400, but will only bedescribed in connection with pupilometer 10 for convenience and brevity.It should be understood, however, that each of pupilometers 10, 300, and400 are hand-held devices having similar dimensions, and the consensualmeasurement apparatus described herein can be used with each of them.

Turning now to FIG. 9, a pupilometer 10 in accordance with the presentinvention may incorporate a consensual measurement apparatus or armature50 to enable consensual pupilary responses to be analyzed. In apreferred embodiment, the armature 50 may detachably engage a main body11 of the pupilometer 10. However, as explained above, the armature 50also may be permanently affixed to the main body 11 of the pupilometer10.

One test for analyzing consensual pupilary responses is commonlyreferred to within the medical community as a “swinging flashlighttest.” During a typical swinging flashlight test one eye of a subject ismonitored, and a visible light stimulus is applied first to the eye ofthe patient that is being monitored, then to the eye of the patient thatis not monitored and, finally, again to the eye that is monitored. Ifthe eyes of the patient are normal, the pupil of the monitored eyeshould constrict in response to all of the light stimulus pulses(regardless of which eye the stimulus pulse is applied to). Followingapplication of the first light stimulus, the pupil of the monitored eyeshould begin to dilate, and upon application of the second lightstimulus (i.e., upon application of stimulus to the non-monitored eye),the pupil of the monitored eye should again constrict. If the monitoredpupil does not respond adequately to the second stimulus pulse, it maybe inferred that the retina of the non-monitored eye somehow may beimpaired. If the monitored pupil does not respond adequately to thethird stimulus pulse, it may be inferred that the retina of themonitored eye somehow may be impaired.

By using a consensual measurement attachment 50 in accordance with thepresent invention, it is possible to perform a “swinging flashlight”test using the pupilometer 10. For example, when performing a “swingingflashlight” test, the P-program may first cause the yellow LEDs 26within the pupilometer 10 to be activated for a period of, for example,1 second. The P-program then may deactivate the yellow LEDs 26, and 0.5second following deactivation of the yellow LEDs 26 may activate for 0.5second the yellow LED 52 located at the distal end 54 of the consensualattachment. Finally, after deactivating the yellow LED 52 and waitingfor a period of, for example, 0.5 second, the P-program may againactivate the yellow LEDs 26 for a period of 1 second. Image frames maybe obtained by the imaging sensor 14 at a rate of, for example, 10frames per second and for a total period of 5.0 or more seconds toevaluate the consensual response of the imaged eye. If desired, theprocess may be repeated a predetermined number of times.

E. Miscellaneous System Calibration and Pupil Identification ProcessingTechniques

The following system calibration and pupil identification processingtechniques are applicable to pupilometers 10, 300, and 400, but willonly be described in connection with pupilometer 10 for convenience andbrevity. It should be understood, however, that just as with the abovedescription of the software, the techniques described now can be usedwith pupilometers 300 and 400 as well.

In alternative embodiments, the P-program of a pupilometer 10 inaccordance with the present invention may incorporate a calibrationalgorithm that uses acquired data descriptive of the perimeter of theiris 37 of the eye 38 of a patient to define a relationship betweenpixel spacing data and real world measurement parameters and/or toevaluate an orientation of a patient's eye 38 in relation to thepupilometer 10.

For example, in one innovative aspect, the P-program of a pupilometer 10may cause the iris of the eye of a patient to be illuminated by bluelight (i.e., may activate the blue LED 28) and, while the patient's eyeis so illuminated, may obtain an image of the sclera/iris border of thepatient's eye. A flying spot or similar processing algorithm may then beused to identify a best fitting elliptical circumference for thesclera/iris border of the patient's eye, and the radii or horizontal andvertical diameters of the circumference may be compared to or correlatedwith assumed sclera/iris border radii or diameters to provide acorrelation between a pixel count and a real world measurement. Forexample, if the horizontal diameter of a sclera/iris border is assumedto be 11.7 mm, and the sclera/iris border measures 117 pixels indiameter, the P-program of the pupilometer 10 may derive a pixelmeasurement to real world correlation factor of 10 pixels/mm, and thatcorrelation factor may be used to provide the user with pupilmeasurement information. In accordance with one preferred form of thepresent invention, the horizontal diameter of the sclera/iris border isassumed to be 11.75 mm for in all subjects. However, those skilled inthe art will appreciate that a different diameter, such as 11.0 mm or12.0 mm, may also be assumed.

Similarly, by evaluating the shape of the sclera/iris border of an eyeit is possible to estimate the angular orientation of the eye withrespect to the pupilometer 10 and, moreover, to evaluate the orientationof an eye with relation to a vertical axis of the eye. Preferably, thismay be done by evaluating a degree of ellipticity of the imagedsclera/iris border and assuming that the shape of the sclera/iris borderhas a predetermined elliptical shape. Such, measurements may be furtherrefined by comparing the shape of a pupil to the shape of a surroundingsclera/iris border to determine whether variations in the shape of apupil arise from angular orientation of the eye in relation to thepupilometer 10, or from non-uniformities or irregularities in theperimeter of the pupil.

In another innovative aspect, a pupilometer 10 in accordance with thepresent invention may include software for utilizing physical landmarksto assist in locating a pupil within an image data frame. In such anembodiment, the feature extraction object 106 of the P-program executedby the microprocessor (not shown) may include code for identifyingcharacteristic structures of ocular tissue such as eyelids and/oreyelashes within an image data frame, and for using the location ofthose structures to predict the location of a pupil within the imagedata frame. Additional landmarks that may be located in accordance withthe present invention include the lachrymal punctum, lachrymalcaruncula, and lateral and medial papebral commisures of a patient'seye. These landmarks also may be used to identify which eye of a patientis being monitored.

F. Diagnostics Systems and Methods in Accordance with the PresentInvention

In still another innovative aspect, the present invention is directed toimproved diagnostics systems and methods incorporating a pupilometer 10and medical database (not shown). For example, it is contemplated inaccordance with the present invention that data representative of aplurality of pupilary response or configuration characteristicsassociated with one or more physical or pathological conditions may bestored within a medical diagnostics data base, that a pupilometer 10 maybe used to obtain data descriptive of one or more pupilary response orconfiguration characteristics from a patient, and that the obtained datamay be compared to the stored data within a data analysis system toidentify one or more physiologic or pathologic characteristics orconditions of the patient. Further, in a preferred form, the obtainedand/or stored pupil configuration data may be descriptive of one or morestatic or dynamic regional non-uniformities that may exist within theperimeter of a patient's pupil.

One example is a medical diagnostics system, as shown in FIG. 10,wherein the pupilometer 300 can be used to screen for Glaucoma. Thepupilometer 300 can comprise a diode array 340 having a diffuse yellowlight emitting surface 310 in conjunction with series N concentrated(optically) blue LEDS 320 which are imaged onto the retina of an eye insuch a way as to illuminate N specific regions. A single on-axis red LED350 can also be used as a fixation target to assure consistent retinalstimulus. The diode array 340 is also shown in FIG. 11 in atwo-dimensional frontal or overhead view.

Sensitivity and accuracy of Glaucoma detection are improved by thissystem and method, which employs the diffuse yellow light emittingsurface 310 in order to bias the background as yellow and the Nconcentrated blue LEDS 320 as flicker sources for stimulating the retinaof the eye. Alternatively, the background light can be white while thesource of flicker light can generate green light. Again, the IR LEDS areactivated to illuminate the eye and enable the imaging sensor to detectpupilary response to the stimluatory light, i.e., the blue or greenlight.

The microprocessor 34, as shown in FIG. 1, controls the operation andfunction of this illumination system as previously described. Thesubject patient's point-of-gaze is verified for each measurementutilizing the tracking features of pupilometer 10. The pupilary responsefor each of N blue (or green) illumination regions is documented andcompared to a database of normal measurements to determine if theresponse falls out of range. Alternatively, the pupilary response foreach of N blue (or green) illumination regions can be compared to adatabase of measurements that indicate Glaucoma to determine whetherthey fall within those measurements and therefore indicate Glaucoma.Both amplitude and velocity of pupilary response is detected by theimaging sensor 14 and recorded by the image signal processing board 34.It is expected that in the presence of Glaucoma peripheral retinalresponse to blue (or green) light stimulus will be compromised.

The pupilometer 10 can also be used to diagnose elevated intracranialpressure. Under conditions of elevated ICP, the profusion of theocculomotor nerve (CNIII) is compromised, therefore affecting thepropagation properties of action potentials through nerve fibers.Therefore, under amplitude modulated conditions, which elicit maximalpupilary response, the dynamic properties of the light-reflex as afunction of time will deteriorate to a greater extent in thoseindividuals with elevated levels of intracranial pressure. Thestimulus/illumination object 102 can be amplitude modulated, and eitheror both the blue LEDS 28 and the yellow LEDS 26 can act as the stimulussource and can be amplitude modulated also. In this embodiment, thestimulus/illumination object 102 can control the amplitude of thestimulus source to repeatedly cycle the pupil reflex. The pupilometer 10can be used to capture a sequence of images of the eye while acontinuous and amplitude modulated light stimulus is applied to the eye,either by the blue LEDS 28 or the yellow LEDS 26. The P-program softwaredetects the pupil margin and calculates the average rate of change ofthe pupil as a response to an extended duration amplitude modulatedlight stimulus source. The average rate of change data is then comparedto normative or previously recorded data for the patient or a normalsubject as an indicator of abnormality and CNIII involvement due toelevated intracranial pressure.

When the amplitude of the light projected to the eye is increased, theconstriction velocity of the pupil should increase. But, theconstriction velocity for each successive increase in light stimulusamplitude is generally lower in those individuals who are diagnosed withelevated intracranial pressure. On the other hand, as the amplitude isdecreased, dilation velocity in individuals with intracranial pressureincreases at a more rapid pace. Thus, constriction and dilationvelocity, as well as pupilary amplitude, can be used to determinewhether an individual has elevated levels of intracranial pressure.

The pupilometer 10 can also be used to diagnose impairment to brainfunction. The task of fixating on a target and maintaining this fixationas the target is moved about the visual field requires constant corticalfeedback and cerebellar eye movement correction. The ability to visuallytrack a moving target can be assessed by tracking actual point-of-gazeand comparing this information to a stored expected value for a setpattern of target movement. Substantial deviation from the expectedvalue is an indication of brain disorder. Alternatively, the storedexpected value can represent brain function impairment rather thanrepresenting a normal brain with no brain function impairment. In thiscase, values that fall within the range of the stored expected valuerepresent brain function impairment. In addition, simultaneouspresentation of multiple target points in the visual field has apredictable effect on paint of gaze for normally functioning brains evenat a young age. Deviation from the predicted behavior to multiple pointtargets may give rise to the early diagnosis of Autism.

The system for diagnosing impairment to brain function comprises apupilometer, such as the pupilometer 300 shown in FIG. 10, a moveabletarget or light source, a database for storing data descriptive of oneor more pupilary characteristics associated with a set pattern of targetmovement, and a central processing unit coupled to the pupilometer. Thetarget may be on the pupilometer itself, and may be comprised of a lightgenerated by a visible light source, or any other visible object. Forexample, the pupilometer 300 may have a diode array such as the diodearray 370 shown in FIG. 13, which is similar to the diode array 340 usedfor glaucoma detection. The main difference between the two diode arraysis that the diode array 370 has more LEDS fixed onto a yellow lightemitting surface 380 defining a surface area the same or similar in sizeto the surface area of light emitting surface 310 of diode array 340.Individual elements or LEDS 390 of the diode array 370 can besequentially turned on and the subjects pupillary movement analyzedaccording to the subjects ability to track the apparent motion of theLEDS.

The point-of-gaze is determined by detecting features of the eye inaddition to the pupil and using fiducial alignment references generatedby the system. The P-program will generate a frame by frame history ofthe point-of-gaze and compare the test results to a figure-of-merit fora normal brain given the same set of visual stimuli. Ultimately thesystem will indicate the type of tracking error that occurred (i.e.,degree of overshoot, magnitude of lag, static dwell time) each of whichindicate specific brain disorders.

The pupilometer 10 of FIG. 1 or the pupilometer 400 of FIG. 13 can alsobe used to test the functional integrity of afferent peripheral andcranial pathways as well as testing efferent cranial nerve involvementin patients with afferent pupilary defects. The pupil is mediated by acomplex control system for which the output (pupil size) is determinedby the sum of various autonomic inputs. The autonomic inputs that affectthe pupil include both sympathetic and parasympathetic constituents.Noxious stimulation such as a pin-prick, sudden exposure to hot or cold,electrical current or pinching should result in a pupilary response. Theresponse may include pupilary amplitude response to pain, reflexivepoint-of-gaze eye-movement or reflexive blinking.

In the pupilometer testing system described herein, the pupil isobserved under a constant background light condition, such as IR lightfrom IR LEDS 24 (or 424 on pupilometer 400), or yellow light from yellowLEDS 26 of the pupilometer 10. Meanwhile, noxious stimulation from anoxious stimulus source 17 is presented to the subject patient, and thisstimulation is controlled with precise timing by the pupilometer'smicroprocessor 34 (or 434 on pupilometer 400), which is in electricalcommunication with the noxious stimulus source 17 through auxiliaryconnector 15 (or 415 on pupilometer 400). The magnitude, direction ofgaze and temporal characteristics of the eye response including blinkingare determined by image processing means in the P-program software.Sources of noxious stimuli, which are controlled by the pupilometerwithout exposing the patient to tissue damaging effects, include briefpulses of air, release of small bursts of cryogenic spray, such asHalocarbon 134a, and small electrical currents. These stimuli areapplied to various dermatopic areas in addition to afferent-sensoryareas such as the tympanic membrane and the cornea, which are innervatedby cranial nerves.

The noxious stimuli are generated by a noxious stimulus source 17connected to the pupilometer 10 by auxiliary connector 15 (or auxiliaryconnector 415 on pupilometer 400). For dorsal root and spinal cordinvolvement a small canister of compressed CO2 gas with anelectronically controlled regulation valve is electrically coupled tothe auxiliary connector or output port 15 on the pupilometer 10 (or 415on pupilometer 400). The valve releases a metered volume of CO2 gasproviding a source of extreme cold which can be directed to anydermatome area. The pupil is evaluated for the pain/cold response atprogressively lower dermatopic areas until a differential in pupilaryresponse is detected. The P-program software calculates/detects thepupil margin and calculates the gross rate of change of the pupil as aresponse to the noxious stimulus.

The corneal-blink reflex, which is mediated by afferents of theophthalmic branch of the trigeminal nerve (CNV) can be tested by thesystem using compressed air or a fan which produces a small puff of airon the cornea while the P-program monitors pupil as well as eyelidresponse.

The eye moves away from an ice water stimulus on the tympanic membranein the ear. A cryogenic spray can produce the same behavior via noxiousstimulus to the ear. A CO2 canister and regulated valve as describedearlier and electrically coupled to the pupilometer 10 or thepupilometer 400, is used to measure the eye movement in response to thistympanic membrane stimulation.

Finally, the pupilometer 10 or the pupilometer 400 can also be used inconnection with a system for testing the functional integrity ofauditory pathways (vestibulocochlear nerve and the auditory cortex) bydetecting pupilary response to sound stimulus. In this implementation ofa pupilometer-based hearing testing system, the pupil is observed undera constant background light condition while an audible stimulus ispresented to the subject or patient. This stimulus is controlled withprecise timing, amplitude and frequency by the pupilometer's 10microprocessor 34 (or 340 on pupilometer 400). The amplitude andtemporal (i.e., velocity) characteristics of the pupilary response aredetected by the imaging sensor 14 (or 414 on pupilometer 400) andrecorded by the microprocessor 34 (or 434 on pupilometer 400).

This aspect of the invention can also be implemented by a systemcomprising a pupilometer as described herein, a sound generatingtransducer capable of generating sound in various amplitudes andfrequencies and in electrical communication with one or more ear-piecesor speakers 19, as shown in FIGS. 1 and 13, a database for storing datadescriptive of one or more pupilary characteristics associated with aset pattern of sound stimuli, and a central processing unit. The datastored in the database can represent pupilary responses that are normaland indicative of healthy auditory pathways, or can represent pupilaryresponses that represent abnormal or disfunctional auditory pathways. Ineither case, a comparison of the data representing the patient's orsubject's pupilary response to the data stored in the database, usingthe central processing unit, can determine the functional integrity ofthe patient's auditory pathways.

In another embodiment, an algorithm associated with the memory ofmicroprocessor of the pupilometer, or the memory or microprocessor incommunication with the pupilometer, identifies two or three phases thatapplicant has discovered characterizes a normal or canonical pupil light(or other stimulus) constriction reflex. A canonical reflex is one whichis expected from a healthy or normal pupilary reflex response. A healthyor normal pupilary response from a pupil subjected to a stimulus, suchas a light stimulus, e.g., a flash of light, or any other stimulusdescribed above, has a period of latency followed by constriction and aperiod of remaining constricted, followed by dilation back to theoriginal resting dilation.

Stated in more detail, applicant has discovered that the followingphases occur immediately subsequent to subjection of the pupil to astimulus, such as light, or any other stimulus described above. Phase 1characterizes a latent period following the onset of the light (orother) stimulus (see FIG. 14A). Phase 1 starts at time 0 and has aduration of greater than about 100 msec and less than about 1000 msec.During this latent period the pupil has not yet started constricting andits diameter does not change considerably. The constriction, or phase 2,starts usually only at least 180 or 200 msecs after the onset of thelight stimulus and it is characterized by a significant decrease of thepupil diameter. After the constriction, there might be a third phaseduring which the pupil recovers and tends to return to its initialstarting diameter. The pupil diameter during phase 1 is always greaterthan the pupil diameter during phase 2, and the pupil diameter duringphase 2 is always smaller than the pupil diameter during phase 3.

If these two (or three) phases are not identified by the pupilometer,the analyzed pupil profile does not resemble a canonical pupil lightreflex. Thus, using the method and system described herein, thepupilometer can determine whether the pupil reflex is characteristic ofa canonical pupil light reflex. If not, the pupilometer will provide anoutput indicating that the pupil reflex is not a canonical pupil lightreflex.

The first step of the algorithm is a low pass noise reduction filteringthat removes all the physiological and instrumental noise from the pupildata profile (see the profile in FIG. 14B after the low pass noisereduction operation). Then the algorithm tries different horizontal cutsof the pupil profile; it starts from the very top of the profile (seeFIG. 14C) and then goes down step by step with small decrements; foreach possible position of the horizontal cut (see dotted line X in FIGS.14C and 14D) the algorithm tries to validate the following conditions:

-   -   a. there is only one (or at most two intersections) between the        pupil profile and the horizontal line (see the small circles Y1        and Y2 in FIG. 14D).    -   b. during phase 1 (before the first intersection, e.g. first        circle Y1 in FIG. 14D) the pupil diameter is all above the        horizontal line. In other words, immediately subsequent to        stimulation of the pupil with a stimulus source, such as light,        or any other source described above, the pupil diameter does not        increase before it decreases.    -   c. the duration of phase1 must be a certain duration of time z.        In one embodiment, z is a figure between 260 msec and 1 second.        In another embodiment, z is a figure between 100 msec and 1        second. In yet another embodiment, z is a figure between 200        msec and 1 second. In yet another embodiment, z is a figure        between 320 msec and 1 second.    -   d. if there is more than 1 intersection between the pupil        profile and the horizontal line, then the duration between the        first intersection and the second intersection must be equal to        or greater than a duration of time t as measured in milliseconds        (msec). In one embodiment, t is 260 msec. In other embodiments,        t is 100 msec, 200 msec, 300 msec, 320 msec, 400 msec or        greater.        Put another way, the algorithm tries to validate the following        conditions:    -   a. no more than two data points exist representing the same        pupil diameter at separate times during duration y, which can be        between about 1 and about 4 seconds;    -   b. a first phase of the pupilary reflex response exists, wherein        said first phase is characterized by a period of        non-constriction immediately subsequent to time 0 (the onset of        stimulus), said first phase having a duration of greater than        about 100 msec and less than about 1000 msec;    -   c. if two data points exist representing the same pupil diameter        at two separate times y¹ and y² during duration y, then the        duration of time between y¹ and y² is greater than about 100        msec; and    -   d. during the first phase of the pupilary reflex, the diameter        of the pupil does not increase before it decreases;

If the algorithm does not find any cut where all of these fourconditions are valid, then the algorithm fails and the pupil profilesummary or output concludes that the pupil reflex does not resemble acanonical pupil light reflex.

FIGS. 14E and 14F show examples of a non canonical pupil profileaccording to the present invention. FIG. 14F is the low-passed versionof FIG. 14E. In this example, none of the possible horizontal cutsvalidate the four conditions together. The pupil diameter is measured inmillimeters.

The pupilometer can be used to issue the stimulus, or control ormodulate it, and it can also be used to image and record the response ofthe pupil to the stimulus. The graphs shown in FIGS. 14A-14E can begenerated by the pupilometer using the algorithm and a low pass filterintegrated with the pupilometer or accessed by the pupilometer. Thus,the pupilometer can track the pupil's constriction response over aduration of time starting from a time 0 and lasting for a period of timey. The pupilometer can then collect a plurality of data points, eachdata point corresponding with a diameter of the pupil at a specific timewithin the time duration y, and can use those data points to generate apupil data profile by compiling those data points. The pupilometer canuse the above algorithm to then determine whether all of the conditionsa through e set forth above are met. The absence or violation of one ofthe conditions at every cut (see, e.g., x in FIGS. 14C and 14D)indicates that the pupil reflex does not resemble a canonical reflex,and the pupilometer can provide an output or signal that indicates thatthe pupil reflex does not resemble a canonical pupil reflex. Conversely,if all of the conditions are present, then the pupilometer can providean output that indicates that the pupil reflex does resemble a canonicalpupil reflex.

In another embodiment, the pupilometer can use the above algorithm todetermine whether any one of the following conditions are met:

-   -   a. more than two data points exist representing the same pupil        diameter at three or more separate times during duration y;    -   b. a first phase of the pupilary reflex response exists, wherein        said first phase is characterized by a period of        non-constriction immediately subsequent to time 0, said first        phase having a duration of less than about 100 msec or greater        than about 1000 msec;    -   c. two data points exist representing the same pupil diameter at        two separate times y¹ and y² during duration y, wherein the        duration of time between y¹ and y² is less than about 100 msec;        or    -   d. during the first phase of the pupilary reflex, the diameter        of the pupil increases before it decreases.        The existence or presence of at least one of said conditions        indicates that the pupil reflex does not resemble a canonical        reflex, and the pupilometer can provide an output or signal that        indicates that the pupil reflex does not resemble a canonical        pupil reflex. Conversely, if none of the conditions are present,        then the pupilometer can provide an output that indicates that        the pupil reflex does resemble a canonical pupil reflex.

While the invention is susceptible to various modifications andalternative forms, specific examples thereof have been shown by way ofexample in the drawings and are herein described in detail. It should beunderstood, however, that the invention is not to be limited to theparticular forms or methods disclosed, but to the contrary, theinvention is to cover all modifications, equivalents, and alternativesfalling within the spirit and scope of the appended claims.

1-10. (canceled)
 11. A method of assessing a health condition of amammalian subject comprising: using a pupilometer to deliver a stimulusto the subject; an imaging system in communication with the pupilometerto detect and monitor a pupillary response following delivery of thestimulus to the subject; and using a microprocessor in communicationwith the imaging system to receive pupillary response data from theimaging system and to perform the steps of: (a) processing pupil datacomprising pupil diameter measurements as a function of time; (b)determining time values associated with each of a plurality of pupildiameter values; (c) determining whether the following conditions aremet: (i) no more than two data points exist representing the same pupildiameter at separate points in time during a period of no more thanabout four seconds, (ii) a first phase of the pupilary reflex responseexists, wherein said first phase is characterized by a period ofnon-constriction immediately subsequent to stimulating the pupil, saidfirst phase having a duration of greater than about 100 msec and lessthan about 1000 msec, (iii) if two data points exist representing thesame pupil diameter at two separate points in time, then the duration oftime between said two separate points in time is greater than about 100msec, and (iv) during the first phase of the pupilary reflex, thediameter of the pupil does not increase before it decreases; and (d)using the pupilometer to provide an output indicating an abnormal healthcondition if one or more of said conditions (c)(i)-(c)(iv) are not met.12. The method of claim 11, wherein pupilometer provides an outputindicating a normal health condition if all of said conditions(c)(i)-(c)(iv) are met.
 13. The method of claim 11, wherein the stimulusis a noxious stimulus or a light stimulus.
 14. The method of claim 11,wherein the mammalian subject is a human.